Overproduction of thyroid hormone (hyperthyroidism or thyrotoxicosis) is an extremely common clinical entity caused by a number of different pathological conditions of the thyroid gland. Approximately 0.5% of women will experience some clinical manifestation of hyperthyroidism in their lifetime (a frequency 3 to 5 times higher than that occurring in men), with potentially life-threatening effects on the cardiovascular system, including cardiac arrhythmias, heart failure, angina and myocardial infarction, particularly in the elderly1-3.
The treatment of hyperthyroidism has essentially remained unchanged for the past thirty years, and includes the use of radioactive iodine, surgery, or the use of anti-thyroid drugs, such as propylthiouracil, that inhibit thyroid hormone synthesis by blocking the iodination of thyroglobulin1-3. Each approach has its own intrinsic limitations and/or side effects. Propylthiouracil and related drugs, which block thyroid hormone synthesis, act slowly and can take up to six to eight weeks to fully deplete the thyroid gland and intrathyroidal stores of iodinated thyroglobulin, during which time hyperthyroidism can have severe consequences in certain individuals. Radiochemical destruction of thyroid tissues by iodine may require four to six months to be fully effective while surgical thyroidectomy must be preceded with anti-thyroid drugs to prevent life threatening complications such as thyroid storm.
The identification of thyroid hormone receptor (“TR”) antagonists could play an important role in the future treatment of hyperthyroidism. Such molecules would act rapidly by directly antagonizing the effect of thyroid hormone at the receptor level, a significant improvement for individuals with hyperthyroidism who require surgery, have cardiac disease, or life threatening thyrotoxic storm.
As described herein, the present invention addresses the need for novel agents capable of modulating thyroid hormone receptor activity.